Treatment of secondary movement disorders using large neutral amino acids

ABSTRACT

The present invention relates to a method of remitting or attenuating the symptoms of movement disorders which can be secondary to treatment of psychiatric disorders with antipsychotic drugs mainly neuroleptics, movement disorders that arise secondary to non-neuroleptic drugs in the treating of non-psychiatric disorders or primary neurological disorders. This treatment involves administering a meal enriched with large neutral amino acids or a dietary supplement of large neutral amino acids to patients suffering from these disorders.

This is a divisional of application No. Ser. 08/371,211 filed Jan. 11,1995, now U.S. Pat. No. 5,670,539 which is a Continuation-in-Part ofapplication No. Ser. 08/093,955 filed Jul. 21, 1993, now U.S. Pat. No.5,393,784.

FIELD OF THE INVENTION

The present invention relates to the treatment of abnormal movementdisorders through the manipulation of the amino acids in the bloodplasma pool.

BACKGROUND OF THE INVENTION

Neuroleptic drugs, including haloperidol, thioridazine, chlorpromazine,flupenazine and thiothixene, are used as antipsychotics to treat anumber of psychoses, such as schizophrenia, schizoaffective disorder,organic psychosis, bipolar disorder, and unipolar depression (severeform). This represents a sizable portion of Americans, as the NationalInstitute of Mental Health reports that the number of patients in theUnited States with schizophrenia in 1990 was 1.8 million; bi-polardisorder, 1.1 million and unipolar depressives (severe form), 1.7.million. Neuroleptics are also used as behavioral control measures inthe following non-psychotic populations; children with autism, child andadolescent psychiatric patients with conduct and adjustment disorders,,the mentally retarded, and geriatric patients in general hospitals andnursing homes. In these populations, clinical trials have establishedthat these agents are effective in the treatment of symptoms such as;tension, hyperactivity, combativeness, hostility, negativism,hallucinations, acute delusions, poor self-care, and sometimeswithdrawal and seclusiveness. Neuroleptics are also the drug of choiceto treat the symptoms of abnormal, movements in primary neurologicaldisorders; such as for patients with tic disorders (transient ticdisorders, chronic motor tics, Tourettes' disorder) and those withHuntington's Disorder.

Unfortunately, in a large number of individuals, a variety of movementdisorders may develop secondary to chronic neuroleptic treatment therebycreating a therapeutic dilemma in the mental health community. Amongthese disorders are tardive dyskinesia (TD), Parkinsonism, tardivedystonia, akathisia and neuroleptic malignant syndrome.

A similar class of drugs, as represented by the drug methochlorpromide,used as anti-vomiting agents (particularly for cancer chemotherapypatients) are also known to cause a similar set of movement disorders.Additionally, a variety of movement disorders are seen secondary toother drugs such as lithium (used for the treatment of bipolardisorder), anticonvulsants (used for the treatment of seizuredisorders), benzodiazepines (used for the treatment of anxietydisorders) , and tricyclic antidepressants (used for the treatment ofunipolar depression).

Abnormal movements are also seen as primary neurological disorders. Inaddition to the two such conditions mentioned above, tic disorders andHuntington's Disorder, there are many other neurological disorders thatare manifested by abnormal movements; these include, myoclonicsyndromes, childhood and adult onset dystonias, Wilson's disease,Sydenham's Chorea, and other choreas. Several dementias also manifest anabnormal movement component; these include, Alzheimer's disease,Creutzfeldt-Jakob disease, Pick's Disease and Hallervorden SpatzDisease.

The present invention relates to the treatment of abnormal movementdisorders, including those mentioned in the sections above, whether theyare secondary to drug treatment or primary disorders.

These abnormal movement disorders result in a wide variety of symptomswhich can range from unconscious movements which interfere very littlewith quality of life, to quite severe and disabling movements. Examplesof symptoms which are seen secondary to neuroleptic treatment are;involuntary tongue protrusions, snake-like tongue movements, repetitivetoe and finger movements, tremors of extremities or whole body sections,muscular rigidity, slowness of movement, facial spasms, acutecontractions of various muscles, particularly of the neck and shoulderwhich may eventually lead to painful, prolonged muscle contraction,restlessness, distress and an inability to remain still.

Thus, while patients suffering from psychoses such as schizophrenia needtreatment with neuroleptics to control their psychoses, it can bedifficult to integrate these patients back into the mainstream becausethe movement disorder side effects of their neuroleptic treatmentproduce a visual stigma, a stigma which is a barrier to completeacceptance of these patients in the world beyond a hospital or a halfwayhouse.

Consequently, even though neuroleptic treatment may offer the best meansof effectively treating patients who suffer from various psychoses, apervasive fear that one or more of these abnormal movement disorderswill develop and persist exists among psychiatric patients, theirfamilies and their psychiatrists. This fear results in a psychologicalcap on the therapeutic potential of these neuroleptic drugs to treatpsychosis. It should be noted that the development of TD has been thecause of malpractice suits brought against psychiatrists.

One means of removing this barrier to continued and necessary treatmentwith neuroleptics has been the development of atypical neuroleptic drugs(one of which, clozapine, is available in the U.S.). These drugs areless likely to result in movement disorder side-effects. However,clozapine has some disadvantages relevant to our concerns; it wasdeveloped too late to help some patients, carries the risk of otherserious life-threatening side effects which require expensivemonitoring, and thus is not appropriate to all. For instance, somepublic mental health facilities, because of cost issues, mustnecessarily limit the use of this drug to only a small segment of thepopulation that they treat.

The present inventor has conducted a 15 year course of study inneuroleptic-induced abnormal movement disorders. This work isrepresented by the work she has done to define the etiology,pathophysiology, and to develop treatment and preventive strategies forone of the neuroleptic-induced movement disorders, TD. The researchstrategy in this facet of her work was to define risk factors for thedevelopment of this disorder in all the major neuroleptic treatedpopulations (adult psychiatric patients, geriatric psychiatric patients,child psychiatric patients and the mentally retarded), to search forcommonalities in these risk factors across populations and then tointegrate these findings into a unitary biochemical paradigm for thepathophysiology of TD. The unitary paradigm that was generated from thedata of these studies defines the metabolism of the large neutral aminoacid, phenylalanine, as a pathophysiologic element in TD. The individualstudy findings that most directly led to this paradigm were those of alarge scale point prevalence study of TD among mentally retarded (notpsychotic) residents (n=211) of a state developmental center (StudyOne--see below). In that study the inherited metabolic disorderphenylketonuria (PKU) was found to be a strong and statisticallysignificant risk factor for TD development. The power of that riskfactor was demonstrated by the fact that eighty-six percent of thephenylketonurics in the sample had TD as compared to a rate of only 27%of the non-PKU population. This study is seminal in the field ofneuroleptic-induced movement disorder research in that it was the firstreported association of a medical condition (metabolic neurologicaldisorder) with TD and thus provided a new direction for furtherresearch. That direction was the search in the well characterizedpathophysiology of PKU for a clue to the pathophysiology of TD. It iswell known that PKU is an inherited metabolic disease (carried onchromosome 12) in which the activity of phenylalanine hydroxylase, theenzyme responsible for conversion of the large neutral amino acidphenylalanine to tyrosine, is absent or drastically reduced. Thisdeficit creates a condition in which there is a chronic excess ofphenylalanine in the plasma and thus in the brain of PKU patients(Richardson, et al., "The prevalence of tardive dyskinesia in a mentallyretarded population," Psychopharmacol. Bull., 22:243-249, 1986; Scriver,C. R., Kaufman, S. and Woo, S. L. C., "The hyperphenylalaninemias," TheMetabolic Basis of Inherited Disease, edited by Scriver, C. R., Beaudet,A. L., Sly, W. S. and Valle, D. New York, N.Y., McGraw Hill, 1989, pp.495-546).

Given this clue and in the search for a unitary hypothesis acrosspopulations, the present inventor undertook a study to test whether themetabolic response of phenylalanine metabolism to a dietary challenge(protein load) differentiated male schizophrenic patients (the heaviestusers of neuroleptics) with TD from those without the disorder andfurther, whether the metabolic response of the TD patients could becharacterized as PKU-like (Study Two--see below). This means whetherschizophrenic patients with TD would show significantly higher levels ofphenylalanine after the challenge. This was in fact the case with thefinding of significantly higher post challenge levels of phenylalanineand the phenylalanine/large neutral amino acid ratio (LNAA) or aPKU-like response in patients with TD (Richardson, et al., "The plasmaphenylalanine/large neutral amino acid ratio: a risk factor for tardivedyskinesia," Psychopharmacol. Bull. 25:47-51 (1989); "Amino acidmetabolism and tardive dyskinesia vulnerability in schizophrenia",Biological Psychiatry, 2, 341-343 (Excerpta medica, 1991).

A large scale replication (Study Three; n=209 males; n=103 females) ofStudy Two found that the metabolic response to a phenylalanine challenge(100 mg/kg) dramatically and significantly distinguished males with TDfrom those without the disorder, thus establishing phenylalaninemetabolism as a pathophysiological element in TD.

Berry, et al. (U.S. Pat. Nos. 4,252,822 and 4,209,531, and "PRELIMINARYSUPPORT FOR THE ORAL ADMINISTRATION OF VALINE, ISOLEUCINE AND LEUCINEFOR PHENYLKETOURIA," Developmental Medicine and Child Neurology,27:33-39 (1985) and "REDUCTION OF CEREBRAL SPINAL FLUID PHENYLALANINEAFTER ORAL ADMINISTRATION OF VALINE, ISOLEUCINE, AND LEUCINE," PediatricResearch, 16:751-755 (1982)) sought specifically to treat thebehavioral, perceptual and cognitive symptoms of PKU with the branchedchain large neutral amino acids, specifically isoleucine, leucine andvaline (BCAA). The behavioral symptoms, some of which are motor innature, are those of hyperactivity, irritability, poor impulse control,distractibility, aggressivity, and the stereotypical behaviors that arecommonly seen in the mentally retarded such as rocking, jumping,running, spinning, flaying, etc. These investigators found that theseagents (BCAA) were in fact effective in ameliorating many of thebehavioral and cognitive target deficits and with a wider safety marginthan with the routine treatment which consisted solely of a diet low inphenylalanine. In two separate studies, Berry, et al., literature supra,administered BCAA to PKU patients; in the first (two cases) they foundthat the cerebrospinal fluid serum ratio of phenylalanine was reducedand was accompanied by improvements in cognitive function (i.e., motorcoordination and task learning). Cognitive improvement was also noted inthe second study in three patients who had been treated with aphenylalanine restricted diet as infants and who had nearly normal IQs.The authors specifically found improvements in abstract reasoning andtactile-motor problems and coordination, thereby confirming that thesecognitive tasks are particularly sensitive to the biochemical status ofPKU patients. Although the behavioral problems improved by Berry, et al.can involve exaggerated movement, such as running, jumping and flayingmovements; these are sharply distinguished medically from the abnormalmovement disorders, primarily considered to be basal ganglia disease,which are the objectives to be treated herein. Prior to the presentinventor's research, the role of phenylalanine in abnormal movementdisorders seen secondary to neuroleptic treatment, such as TD, wasunknown.

In addition to the work in PKU by Berry, et al., the BCAA as inhibitorsof the uptake of aromatic amino acids at the blood-brain barrier neutralamino acid transport system, are used as therapy for several otherneurological conditions Adibi, et al., "Branched Chain Amino and KetoAcids in Health and Disease," Basil:Karger (1984).

In one of these, hepatic encephalopathy, BCAA treatment is usedsuccessfully to decrease brain transport of the aromatic amino acids(phenylalanine, tyrosine and tryptophan) and of methionine. Two otherdisorders, maple syrup urine disease and isovaleric acidemia, whosepathology involves inability to catabolize the BCAA and thus causeexcess levels of plasma BCAA, are treated by dietary alteration ofplasma BCAA levels. Symptoms of maple syrup urine disease areneurological and include movement disorders (i.e., rigidity) and severemental retardation. Therapy with a diet low in BCAA has been effectiveonly if started immediately after birth.

In addition to the therapeutic use of the branched chain large neutralamino acids in the disorders mentioned above, the aromatic large neutralamino acid, tryptophan has been shown to impact in a complex manner onthe symptoms of abnormal movement disorders. For instance, for themyoclonic syndromes and Tourette's disorder there are reports that bothaugmenting and depressing tryptophan supply to the brain can reducesymptoms (Van Woert, et al., Monographs in Neural Sciences, 3, 71-80,(1976); Avanzini, et al., Monographs in Neural Sciences, 5, 142-152(1980); Jacobs, et al., Gilles de la Tourette Syndrome, eds. Friedhoff,A. J. and Chase, T. N., pp. 93-97, New York: Raven Press (1982)). Thiscomplexity and a further lack of replication has also been seen in theuse of tryptophan for the modulation of TD symptoms. Two case reportsshowed a reduction of TD symptoms following administration ofL-Tryptophan to a patient who was receiving the agent for insomnia; thefinding was repeated in a second patient also being treated for insomnia(Sandyk, R., Consroe, P. F., Iacono, R. P., "L-tryptophan indrug-induced movement disorders with insomnia," N. Engl. J. Med. 1986,314(19):1257;. Sandyk, R., Bamford, C. R., Khan, I. Fisher, H.,"L-tryptophan in neuroleptic-induced tardive dyskinesia," Int. J.Neurosci., 1988, 42:127-130). However, earlier work with seven patientsreported no change in TD with concomitant administration of5-hydroxytryptophan and carbidopa (Nasrallah, H. A., Smith, R. E.,Dunner, F. J., McCalley-Whitters, M., "Serotonin precursor effects intardive dyskinesia," Pharmacology, 1982, 77:234-235) or in 4 patientswith the administration of D-L tryptophan (Jus, K., Jus A., Gautier, J.Villeneuve, A. Pires, P. Pineau, R., Villeneuve, R., "Studies on theaction of certain pharmacological agents on tardive dyskinesia and onthe rabbit syndrome," Int. J. Clin. Pharmacol. 1974, 9(2):138-145).

SUMMARY OF THE INVENTION

Accordingly, an object of the present invention is to provide a methodof treating abnormal movement disorders.

A more specific object of the present invention is to provide a methodof treating abnormal movement disorders which arise secondary to drugadministration, especially secondary to treatment with neuroleptics.

Another more specific object of this invention is to provide a method oftreating abnormal movement disorders which manifest themselves as partof a primary neurological disorder or disease, primarily those of basalganglia disease.

Another object of this invention is to provide a method of treatingtardive dyskinesia (TD), Parkinsonism, tardive dystonia and akathisia.

Another object of the present invention is to provide a method oftreating tardive dyskinesia second ryto neuroleptic treatment.

These and other objects of the present invention have been met by amethod which includes administration to the patient of large neutralamino acids in order to manipulate the amino acid profile of the bloodplasma pool.

In certain preferred embodiments of the present invention, branchedchain amino acids or aromatic amino acids are administered to alleviate(remit or reduce) the abnormal secondary movement disorders which ariseas the result of treatment with a drug.

In a very preferred embodiment of the present invention, branched chainamino acids or aromatic amino acids are administered to alleviatemovement disorders arising secondarily to treatment with neuroleptics.

In certain other preferred embodiments of this invention, branched chainamino acids or aromatic amino acids are administered to alleviateabnormal movement disorders seen as a symptom of a primary neurologicaldisorder or disease.

In a very preferred embodiment of this invention, isoleucine, leucineand/or valine are administered to alleviate the symptoms of the movementdisorder, TD.

In the present invention, all amino acids employed are L-, that is, thenaturally occurring optical isomer configuration.

DETAILED DESCRIPTION OF THE INVENTION

TD is a drug-induced abnormal movement disorder that belongs to a broadcategory of movement disorders known as extrapyramidal movementdisorders. This category generally involves pathology of a group ofsubcortical brain structures known collectively as the basal, ganglia,as distinguished from other movement disorders caused primarily bydisorders of the cerebral cortex, spinal cord, cerebellum, peripheralnerves or musculature, although in some conditions these other areas maybe involved. In addition to TD, basal ganglia diseases includeParkinson's disease, drug-induced parkinsonism, the choreas, ballism,the athetoses, the dystonias including tardive dystonia, akathisia,Huntington's disease, several degenerative and atrophic syndromes, andseveral toxic and infectious processes.

How the basal ganglia control movements is poorly understood,. butgenerally dysfunction may involve cellular loss, metabolic dysfunctionor dysregulation of electrical-type input/output balance. Some of thesedefects may be compensated for by manipulation of neurotransmittersynthesis or release; one way this can be achieved is by dietary controlof the supply of neurotransmitter precursor amino acids at the bloodbrain barrier as the blood brain barrier has transport systems thatmediate the bi-directional flux of amino acids. The majorneurotransmitter precursor amino acids enter the brain via the L-system(the L stands for "leucine") which transports neutral amino acidsbetween blood and brain in a competitive manner.

In addition to the Richardson, et al. work showing that TD may involverelatively higher levels of the amino acid phenylalanine, this aminoacid has been shown to be elevated in the cerebrospinal fluid ofParkinson's disease, senile dementia, dystonia musculorum deformans,chore& athetosis, and essential and hereditary tremor (Lakke & Teelken,Neurology, 26, 489-493 (1976)). Thus, amino acid transport defectsinvolving phenylalanine may be common to a number of neurologicaldisorders, and the action of a dietary supplement of large neutral aminoacids can be seen as an effective, and efficient potential treatmentacross a broad range of neurological disorders.

The public health consequences of TD have driven researchers to thegeneration of a large body of research trying to unearth thepathophysiology of the disorder. These studies have led to diversehypotheses which focus on dopaminergic (Bowers, et al., J. ClinicalPsychopharmacol., 7:57-58 (1987); and

Seeman, P., J. Clinical Psychopharmacol., 8 (4, supp):3s-9s (1988)),noradrenergic (Jeste, et al., Br. J. Psychiatry, 144:177-180 (1984);Wagner, et al., J. Clinical Psychopharmacol., 2:312-314 (1982); andKaufman, et al., Biol. Psychiatry, 21:799-812 (1986)), gabaergic(Tamminga, et al., Arch. Gen. Psychiatry, 6:595-598 (i979); Fibiger, etal., TINS, pp. 462-464 (Dec. 1984); Thaker, et al., Arch. Gen.Psychiatry, 44:522-529 (1987); Stahl, et al., Biol. Psychiatry,20:888-893 (1985); Andersson, et al., Mov. Disord., 4(1):37-46 (1989);Thaker, et al., Biol. Psychiatry, 25:49-59 (1989); and Gunne, et al.,Nature, 0:347-349 (1984)), or free radical mechanisms (Lohr, et al.,Schizophr. Bull., 14:291-296 (1988); and Cadet, et al., Ann. NY Acad.Sci. 5:176-185 (1989)).

These above-mentioned proposed mechanisms have been evaluated based onmeasurements of the correlation of various biochemicals, such asdopamine, norepinephrine, serotonin, their respective metabolites andproducts of free radical peroxidation thereof, which are measured in theplasma, urine and cerebrospinal fluid of patients with symptoms of TD.However, most often, these correlations are inconsistent with clinicalobservations and the results of treatment trials based on the postulatedmechanisms.

In one study of several neurochemical correlates of tardive dyskinesia,the researchers found no associations between the absolute levels ofmonoamine metabolites of these chemicals in cerebrospinal fluid, and thestatus of the patients' TD. However, this study did note significantreductions in the ratios of various neurotransmitter metabolites in thecerebrospinal fluid (Lu, et al., Biol. Psychiatry, 25:717-724 (1989)).

Overall, the previous work done in this area suggests that themanifestation of abnormal movement disorders such as TD, at minimuminvolve several neurotransmitter systems, and that vulnerability to suchdisorders, particularly upon treatment with neuroleptic drugs, may bemultifactorial.

The present inventor has performed several studies relating toneuroleptic-induced movement disorders in her 15 years in the field. Inboth her research and in her clinical work directing a Clinical MovementDisorders Program for the New York State Office of Mental Health she hasevaluated and recommended treatment for several hundred patientssuffering from such disorders. As described in the Background sectionabove, the prelude to the present invention were several large scaleepidemiological studies across several populations which had beendesigned by the present inventor to uncover risk factors for TD thatcould be used to define a unitary pathophysiological etiology for thedisorder. One of these studies, in the mentally retarded, in findingthat patients with PKU when treated with neuroleptic drugs were atparticular risk for TD led to a consideration of the role of thearomatic large neutral amino acid, phenylalanine in TD. This study(Study One) was the first in a series of four investigations that ledmost directly to the present invention since it is known that in PKU theprimary and causative defect is that phenylalanine is in excess inplasma and brain. Schizophrenia being the diagnostic category ofpsychotic disorders for which neuroleptics are most heavily prescribed,the present inventor then in a second study (Study Two) tested whetherplasma phenylalanine levels would differentiate 53 male schizophrenicswith TD from those without the disorder. Since it is known that thesepatients were not phenylketonurics and any defects in phenylalaninemetabolism would necessarily be subtle, a protein challenge was used inan attempt to separate out patients whose phenylalanine metabolism couldbe a TD risk factor. It was found that the metabolic response to aprotein challenge significantly discriminated patients with TD fromthose without the disorder in that those with TD had statisticallysignificantly, higher levels of phenylalanine and a statisticallysignificant higher phenylalanine/large neutral amino acid ratio afterthe challenge. This finding was independent of the age of the subject.

A third study (Study Three) was a large scale replication of Study Twowith some improved technical methodology; most importantly, the switchfrom a protein challenge to a phenylalanine challenge and the weightstandardization of the phenylalanine challenge (100 mg/kg). Thisinvestigation was conducted in 209 psychotic males and 103 psychoticfemales. It was found that the phenylalanine challenge produced an evengreater separation of TD Yes and TD No groups than had occurred in StudyTwo with again the TD Yes patients having statistically significanthigher levels of both plasma phenylalanine and the phenylalanine/largeneutral amino acid ratio. This finding was independent of the age of thepatient.

In this work (Study Two and Three) the plasma level tells us the actuallevel of phenylalanine in the blood and the phenylalanine/large neutralamino acid ratio gives us a marker relative to the other large neutralamino acids. This ratio thus provides information on brain levels ofphenylalanine, or more specifically, the penetrance past the blood brainbarrier of phenylalanine. This is so because it is known thatphenylalanine competes with the other large neutral amino acids, such astyrosine, tryptophan, isoleucine, leucine and valine for entry into thebrain across the blood brain barrier. Moreover, of these large neutralamino acids, phenylalanine has the highest affinity for the blood brainbarrier (Pardridge, W. M., In: Wurtuan, et al., eds., Nutrition and theBrain, Volume 7: 199-241, New York: Raven Press (1986)). As a result,higher plasma levels of phenylalanine will lead to correspondingly lowerbrain levels of the neurotransmitter precursors tyrosine and tryptophanthus leading to lower levels of the neurotransmitters, dopamine,norepinephrine and 5-hydroxytryptophan (serotonin). Higher levels of themetabolites of phenylalanine inhibit the activities of tyrosinehydroxylase, tryptophan hydroxylase, and dopa decarboxylase which alsoleads to lower levels of these neurotransmitters. The relatively lowerlevels of serotonin and dopamine due to the higher levels of plasmaphenylalanine and the phenylalanine large neutral amino acid ratio arebelieved related to the present invention since serotonin, dopamine, andserotonin-dopamine interactions are known to be of critical importancein movement control.

As a result of the three studies discussed above, the present inventorhypothesized for the first, time that the levels of phenylalanineaccumulated in the plasma and tissues of psychiatric patients play arole in whether such a patient will develop abnormal movement disorders,such as tardive dyskinesia, secondary to treatment with neurolepticdrugs.

More specifically, the present inventor believes that patients with TDmay be experiencing small, but regular relatively higher elevations inplasma phenylalanine. These higher levels may be sufficient to effect adecreased transport of the competing aromatic amino acids, tyrosine andparticularly tryptophan, into the brain. She speculates that thesubstance of TD vulnerability may be these relatively higher levels ofplasma phenylalanine which by interfering primarily with tryptophantransport, may create primarily a hyposerotonergic and secondarily ahypodominergic neurochemical substrate. One of her further speculationsis that this hyposerotonergia may be particularly important resulting ina physiological supersensitivity which when aggravated by neuroleptictreatment, may lead to TD. The present inventor has interpreted some ofthe data in the literature which suggests a strong inverse relationshipbetween plasma phenylalanine and brain serotonin to support thisspeculation. One such study shows reduced synthesis of serotonin in mildhyperphenylalaninemics who are under good metabolic control and who havenormal development without neurological signs or EEG abnormalities(Giovannini, M., Valsasina, R., Longhi, T., Cesura, A. M., Galva, M. D.,Riva, E., Bondiolotti, G. P., Picotti, G. B., "Serotonin andnoradrenaline concentrations and serotonin uptake in platelets fromhyperphenylalaninemic patients," J. Inherited Metab. Dis. 1988,11:285-290). Further, increased cerebrospinal levels of phenylalanineare associated with decreased CSF levels of tryptophan and itsmetabolites in schizophrenics with no known defects in phenylalaninemetabolism (Bjerkenstedt, L., Edman, G., Hagenfeldt, L., Sedvall, G.Wiesel F. A., "Plasma amino acids in relation to cerebrospinal fluidmonoamine metabolites in schizophrenic patients and healthy controls,"Br. J. Psychiatry, 1985, 147:276-282).

Most proximal to the present invention, however, was an unexpected StudyTwo finding. Within two hours after the high protein challenge meal richin branched chain amino acids, the TD symptoms of patients with chronicTD were either greatly attenuated or totally remitted in greater than50% of the 42 patients with the disorder. The plasma amino acid datacollected and analyzed at the very point of the TD symptom remissiongave the present inventor a clue that it was the branched chain aminoacid enriched meal that caused this remission, and further that theremission was due to a temporary relief of the imbalance in theserotonin-dopamine interactions contributed to by a depression of thetransport of tryptophan into the brain. The following Example 1 presentssome of the details of Study Two which allow for an understanding ofthese unexpected findings of TD symptom remission which are mostrelevant to the present patent application. The following Examples areprovided, however, for illustrative purposes only, and are in no wayintended to limit the scope of the present invention.

EXAMPLE 1

In this study, 53 male schizophrenics were enrolled. In the last fewmonths of the investigation 17 female schizophrenics were also enteredinto the study in order to collect pilot data on females. The numbers offemales were insufficient, however, to allow for statistical analysis.

The protocol employed is also described in the aforementionedRichardson, et al. publication in Psychopharmacol. Bull., Vol 25, No. 1,1989, p. 47; although the unexpected TD symptom remission data was notincluded in that paper nor is it yet to be published.

Blood samples were drawn from patients after an overnight fast and 2hours after the ingestion of a protein challenge. This challenge wasserved in the form of a breakfast which consisted of orange juice, acheese omelette, ham, a waffle and coffee. The breakdown of the meal was74.0 g of protein, 89.3 g of fat, and 42.1 g of carbohydrates which wasequal to 3.6 g of phenylalanine, 0.9 g of tryptophan, and 15.9 g ofBCAA. The mean weight of a study patient was 75.4 kg; thus, the meanphenylalanine load per subject was about 50 mg/kg and the mean BCAA loadwas about 209 mg/kg (formulated of 57 mg/kg of isoleucine, 62 mg/kg ofvaline and 90 mg/kg of leucine).

The post-dietary challenge blood plasma samples were measured 2 hoursafter the challenge because data from a series of acute phenylalaninedosing studies showed that most of the subjects' showed peakphenylalanine plasma levels at a time point that is 2 hours afterchallenge administration (Stegink, L. D., In: Stegink, et al., eds.,Aspartame Physiology and Biochemistry, New York: Marcel Dekker, pp.509-553 (1984)).

For this same reason, TD was also rated at this 2 hour after challengetime point. Patients were again evaluated for their TD status at a timesubsequent to the evaluation session.

The blood samples were assayed for the levels of plasma large neutralamino acids; phenylalanine, tyrosine, tryptophan, alanine, isoleucine,leucine, valine, histidine, and threonine, and for the levels ofphenylethylamine. The latter was also measured because it is a majormetabolite of phenylalanine and considered to be a neuromodulator.

The plasma amino acids, with the exception of tryptophan, were analyzedby phenylisothiocyanate (PITC) derivation followed by HPLC. The analysisof tryptophan was performed using HPLC with spectrofluormetricdetection.

The plasma values of the amino acids were studied both as actual levelsand as the ratio of phenylalanine level to the level of the other largeneutral amino acids in the plasma. This ratio serves as an index of theentry of phenylalanine into the brain, which accounts for thecompetition of the other large neutral amino acids (LNAA) withphenylalanine (Phe) at the blood brain barrier, as discussed.previously. This ratio is calculated as follows: ##EQU1##

This study showed that greater than 50% of all 42 patients with TD(including males and females) exhibited either remittance or significantattenuation of symptoms at the two hour post protein challenge point.Moreover, several differences were detected in the plasma values betweenthe 30 male patients whose symptoms were or were not remitted (genderdifferences in large neutral amino acid metabolism do not allow formixed sex data analysis and our numbers of females were too small toanalyze separately). In particular, those patients whose TD symptomspersisted had significantly higher post challenge phenylalanine to largeneutral amino acid ratios.

The change in plasma values from fasting to post challenge alsodifferentiated the TD symptom remission group of patients from the TDsymptom persistence group. As seen in Table 1, for these 30 maleschizophrenics there were larger percentage changes in the levels ofphenylalanine, tyrosine, and valine (valine being one of the branchedchain amino acids), in the symptom remission group. In addition, thetryptophan/large neutral amino acid ratios significantly decreased inboth groups, and the decrease was 35% greater in the remittance group.

Thus, the most notable differences were:

(a) that the valine/large neutral amino acid ratio increasedsignificantly in the symptom remission group of patients, but not in thepersistence group;

(b) the phenylethylamine (PEA) level, which is the major metabolite ofphenylalanine, was significantly increased in the symptom persistencegroup of patients, but not in the remission group; and

(c) the magnitude of the decrease in the tryptophan/LNAA ratio wassignificantly greater in the symptom remission group than in thepersistence group.

The present inventor has two complimentary speculations as to how theBCAA enriched meal served to alleviate or reduce TD symptoms. The firstspeculation is that because of the significant decrease in thetryptophan/LNAA ratio seen for the TD remission group the TD remissionmay have been at least partly modulated by the decrease intryptophan/LNAA and resultant decrease in brain serotonin. This positionis supported by the fact that it has been demonstrated in psychiatricpatients that brain serotonin content is dependent on plasma tryptophanlevels (Delgado, P. L., Charney, D. S., Price, L. H., Aghajanian, G. K.,Landis, H., Heninger, G. R., "Serotonin function and the mechanism ofantidepressant action. Reversal of antidepressant-induced remission byrapid depletion of plasma tryptophan,," Arch. Gen. Psychiatry, 1990,47:411-418). The present inventor speculates thus that the decrease inbrain serotonin effected by the decrease in the tryptophan/LNAA mayrelieve over stimulation of supersensitive serotonin receptors, whichmay underlie TD symptomatology. The second speculation is based on theStudy Two data which showed that the patients in whom TD persisted had asignificant post protein challenge increase in phenylethylamine levelsnot seen for the TD remission patients. The present inventor speculatesthat the increase in phenylethylamine acted directly at the serotoninreceptor to maintain TD symptom status quo. The pharmacology ofphenylethylamine has been, extensively studied in animals and that workis helpful to understanding the present inventor's speculation. Oneaspect of this work has shown that phenylethylamine produces a motorsyndrome which can be blocked by serotonin antagonists and prevented bydrugs that cause depletion of serotonin. Thus, it has been suggestedthat phenylethylamine acts directly at serotonin receptors to producethe syndrome (Sloviter, R. S., Connor, J. D., Drust, E. G.,"Serotonergic properties of b-phenylethylamine in rats,"Neuropharmacology, 1980, 19:1071-1074; Dourish, C. T., "Behavioraleffects of acute and chronic b-phenylethylamine administration in therat: evidence of the involvement of 5-hydroxytryptamine,"Neuropharmacology, 1981, 20:1067-1072). The TD persistent patients inStudy Two may chronically experience relatively higher levels ofphenylethylamine in response to the daily intake of protein. Becausethey may produce more phenylethylamine, they may therefore be sensitizedto this trace amine similarly to the animals in the experiment notedabove (Dourish, C. R., "Behavioral effects of acute and chronicb-phenylethylamine administration in the rat: evidence for theinvolvement of 5-hydroxytryptamine," Neuropharmacology, 1981,20:1067-1072). If phenylethylamine works directly at a serotoninreceptor, excess levels may have overridden any benefit from thedecrease of brain tryptophan, contributing to TD persistence.

                  TABLE 1    ______________________________________    Change from Fasting to Postloading    TD Symptom Remission vs TD Symptom Persistence    Mean Values ± SD                           Percent    Fasting     Post-loading                           Change**  L*** P*    ______________________________________    TD Symptom Remission (n = 15)    Plasma Levels****    PEA   87.5 ± 30.5                     92.7 ± 21.8                                +5.9   0.9    PHE   55.5 ± 14.9                     70.6 ± 16.9                                +27.2  3.4  .0045*    TYR   64.8 ± 17.1                     84.3 ± 23.5                                +30.1  3.3  .0047*    TRP   61.7 ± 6.9                     62.3 ± 6.8                                +1.0   0.6    BCAA  413.9 ± 94.5                     569.9 ± 143.1                                +37.8  3.9  .0016*    Plasma LNAA Ratios    PHE   0.076 ± 0.011                     0.074 ± 0.011                                -2.7   -0.5    TYR   0.090 ± 0.022                     0.090 ± 0.020                                0      -0.1    TRP   0.085 ± 0.013                     0.066 ± 0.010                                -22.4  -5.7 .0001*    VAL   0.368 ± 0.055                     0.388 ± 0.059                                +5.4   2.5  .0258*    TD Symptom Persistence (n = 15)    Plasma Levels****    PEA   82.9 ± 19.8                     95.1 ± 19.2                                +14.7  3.1  .0095*    PHE   58.2 ± 11.5                     69.1 ± 11.6                                +18.7  4.0  .0014*    TYR   69.3 ± 14.8                     85.3 ± 22.6                                +23.1  3.2  .0058*    TRP   56.8 ± 8.4                     59.3 ± 13.0                                +4.4   0.9    BCAA  377.8 ± 78.4                     478.5 ± 108.6                                +26.7  3.4  .0047*    Plasma LNAA Ratios    PHE   0.085 ± 0.010                     0.084 ± 0.010                                -1.2   -0.0    TYR   0.103 ± 0.012                     0.103 ± 0.012                                0      -0.2    TRP   0.084 ± 0.016                     0.070 ± 0.012                                -16.7  -3.2 .0072*    VAL   0.340 ± 0.040                     0.348 ± 0.040                                +2.4   1.4    ______________________________________     *Only p values significant according to Holm/Bonferroni procedure listed.     **Postloading/Fasting     ***Matched ttest based on changes from Fasting to Postloading (df = 14).     ****PEA expressed as pg/ml, amino acids as nmol/ml

Overall, including men and women, 21 of 42 patients known to havechronic TD had remission of symptoms when rated two hours afteringesting the protein meal with high BCAA content. An additional 7patients had symptom decreases of 33% or more. As noted, differenceswere seen between the males whose symptoms remitted and those for whomthey did not in the plasma values data analyses presented.

The results of Study Three lead us to think that the finding of 28 outof 42 patients (67%) experiencing either a remission or decrease insymptoms (Study Two) is a technology-restricted finding and with achange in technology the symptom attenuation would be seen in a higherpercentage of patients. In the first place, in Study Two all patientsregardless of their weight were given the same size protein meal. InStudy Three when we used a weight adjusted dose (100 mg/kg) ofphenylalanine, the post challenge metabolic response difference betweenTD Yes/No groups was much stronger statistically than the difference hadbeen in Study Two. Further in Study Two, the BCAA content had to competewith the 3.6 g of phenylalanine for brain entrance; so that inadministering the BCAA alone as a dietary supplement we could expect toimprove our rate of symptom improvement.

While the treatment discovery herein is applicable to female patientssince an equal percentage of males and females (50%) in Study Two (seeabove) experienced a symptom remission after the protein challenge, thesignificant association between plasma indices of phenylalanine and TDwas obtained in males only (Study Three, see above). In that study,which unlike in Study Two had a sufficient number of females (n=103) fora separate analysis, a metabolic response to a phenylalanine challengedid not distinguish females with TD from those without the disorder.Thus, the post challenge levels of Phe and Phe/LNAA ratio havediscriminated TD in males only (Study Two and Three, see above), but theremission potential of the dietary BCAA was observable in 50% of thefemale patients, the same proportion as observed in males (Study Two).While the basis for the gender differences observed are at presentpoorly understood, there is ample evidence that females metabolize aminoacids differently from males (Bremer, H. J., Duran, M., Kamerling, J.P., Przyrembel, H. and Wadman, S. D., Disturbances of Amino Acidmetabolism: Clinical Chemistry and Diagnosis, Baltimore: Urban &Schwarzenberg, 1981; Hagenfeldt, L., Bjerkenstedt, L., Edman, G.,Sedvall, G. and Wiesel, F. A., "Amino acids in plasma and CSF andmonoamine metabolites in CSG: interrelationship in healthy subjects," J.Neurochem., 42(3):833-837, 1984; Bjerkenstedt, L., Edman, G. Hagenfeldt,L., Sedvall, G. and Wiesel, F. A., "Plasma amino acids in relation tocerebrospinal fluid monoamine metabolites in schizophrenic patients andhealthy controls," Br. J. Psychiatry, 147:276-282; Rao, J. L., Gross,G., Strebel, B., Braunig, P., Huber, G. and Klosterkotter, J., "Serumamino acids, central monoamines, and hormones in drug-naive, drug-free,and neuroleptic-treated schizophrenic patients and healthy subjects,"Psychiatry Res., 34:243-257, 1990). These metabolic differences may insome part be due to influences of the menstrual cycle. There are alsoseveral gender-based differences in brain patterns of amino acid derivedneurotransmitters, some of which are present during development and atbirth, others of which assert themselves as a result of sexualmaturation. Therefore, although the plasma levels of phenylalanine atpresent do not serve as a risk factor for TD in females, with furtherinvestigation it might be shown that they do if variability due togender related factors can be controlled for experimentally.Alternatively, a plasma parameter related to phenylalanine metabolismwhich is less sensitive to gender differences may be found for females.Alternatively, a modification of the treatment may be made for femalesif it can be established that the pathophysiology of TD in females isdifferent from that in males. Nevertheless, at present, based onempirical evidence in hand from Study Two, efficacy of the invention isanticipated to be equivalent in both sexes.

EXAMPLE 2

A multi-challenge pilot study (Study Four) with a limited number ofpatients was carried out in order to understand further the unexpectedand therefore uncontrolled finding in Example 1 (Study Two) of theelimination or the reduction of TD symptoms in psychotic patients with ameal rich in BCCA. The multi-challenge study with a tightly controlleddesign found that 3 out of 4 patients showed TD symptom decreases(ranging from 37%-96%) with BCAA dietary supplement challenges; and 6out of 6 patients showed symptom decreases (ranging from 46%-99%) whentaking the same BCAA-rich protein challenge breakfast of Example 1(Study Two).

In this study, 8 male patients were enrolled in an attempt to addressthe following questions:

Study Questions

a) Would a meal of different composition have caused a TD symptomremission?

b) Could we replicate the decrease in TD symptoms seen with the StudyTwo protein challenge meal?

c) Would a dietary supplement of BCAA be an adequate substitute for theStudy Two protein challenge meal?

d) Do the BCAA dietary supplement challenges reduce TD symptoms?

e) Do the patients respond to the phenylalanine challenge with anincrease in TD symptom severity?

Study Procedure

1. A single patient was exposed over a period of several weeks tomultiple dietary challenges, at the rate of one baseline day and onechallenge day per week.

2. The baseline days were Tuesdays and the challenge days wereWednesdays.

3. On both Tuesdays and Wednesdays a videotaped evaluation procedure forTD was conducted and videotaped TD movement count sessions were held.These were 2 hours post-coffee on Tuesday and 2 hours post challenge onWednesday. Movement counts were blindly rated from the videotapes by thepresent inventor.

4. Evaluation sessions were conducted at the same time on both days withpatients fasting (except for one cup of decaffeinated coffee) on thebaseline days.

Study Challenges

1. The Study Two protein challenge breakfast (the same high BCAAbreakfast that produced the TD symptom remission in Example 1).

2. A carbohydrate challenge breakfast; 223 grams of carbohydrates, 1369calories, less than 4% protein.

3. A 100 mg/kg challenge of Phe.

4. A BCAA dietary supplement as follows:

a) 2 patients had 209 mg/kg doses of BCAA powder given in orange juice

b) 1 patient had a 275 mg/kg dose of BCAA powder given in orange juice

c) 2 patients had a flavored formulation containing BCAA 150 mg/kg or275 mg/kg.

The above dosing is in mg/kg patient body weight.

Data that was obtained from this trial on study questions

a) Would any seal have caused a TD symptom remission?

The answer to that question is No.

Four patients ate both the Study Two protein challenge breakfast and ourcarbohydrate challenge meal. Two patients showed an increase in TDsymptoms with one meal and a decrease with the other and two patientsshowed a substantially greater decrease in symptoms with one meal overthe other.

1. Patient A showed a 73% decrease in symptoms with the Study A proteinchallenge breakfast for lateral jaw, choreo/athetoid tongue and lippursing movements. He showed an 88% increase in the same set of symptomswith the carbohydrate challenge meal.

2. Patient B showed a 46% decrease in symptoms with the Study Twoprotein challenge breakfast for choreo/athetoid tongue and lipmovements. He showed a 95% decrease in the same set of symptoms with thecarbohydrate challenge meal. This patient has coexisting TD and tardivedystonia.

3. Patient C showed a 59% decrease in symptoms with the Study Twoprotein challenge breakfast for choreo/athetoid tongue movements. Heshowed an 80% decrease in the same symptoms with the carbohydratechallenge meal.

4. Patient D showed a 62% decrease in symptoms with the Study Twoprotein challenge breakfast for choreo/athetoid tongue movements andtongue protrusions. He showed a 4% increase in those same symptoms withthe carbohydrate challenge meal.

b) Could we replicate the decrease in TD symptoms with the study Twoprotein challenge meal?

The answer to that question is yes, 100% of the patients who ate themeal experienced a decrease in TD symptoms.

Six patients ate the study breakfast and all 6 or 100% experienced adecrease in TD symptoms ranging from 46% to 99%.

The four patients listed above in answer to Question a) showed decreasesin TD symptoms ranging from 46% to 73% two hours after completing theStudy Two protein challenge breakfast.

Two other patients who ate the Study A protein challenge breakfast butwould not eat the carbohydrate challenge showed the following responsesto the Study A protein challenge meal.

5. Patient E showed a 63% decrease in lip movements and a 90% decreasein extremity movements 2 hours after completing the Study Two proteinchallenge breakfast.

6. Patient F showed a 99% decrease in extremity movements 2 hours aftercompleting the Study Two protein challenge meal.

c) Would a dietary supplement of BCAL be an adequate substitute for theStudy Two protein challenge meal:

The answer is yes in 2 out of 3 patients. The one patient for whom theanswer is No has coexisting TD and tardive dystonia.

Three patient had both completed a Study Two protein challenge meal andreceived a BCAA dietary supplement challenge.

1. Patient D showed a 62% decrease in tongue movements with the StudyTwo protein challenge and a 96% decrease in those movements with the lowdose (150 mg/kg) of BCAA in the new formulation.

2. Patient C showed a 59% decrease in tongue movements with the StudyTwo protein challenge and a 57% decrease in those movements with theBCAA in orange juice challenge of 209 mg/kg.

3. Patient B showed a 25% decrease in tongue and lip movements with theStudy Two protein challenge and a 360% increase in those movements withthe BCAA in orange juice challenge of 209 mg/kg. This patient hascoexisting TD and tardive dystonia.

d) Do the BCAA dietary supplement challenges reduce TD symptoms?

The answer is yes in 3 out of 4 patients. The one patient who did not isour same patient with coexisting TD and tardive dystonia.

Four patients received dietary BCAA supplement challenges. Two of those,Patients D and C as shown just above showed decreases of 96% and 57%with BCAA challenges while Patient B showed a symptom increase.

4. Patient G showed a decrease of 12% in chewing movements with the lowdose of the new BCAA formulation (150 mg/kg) and showed a decrease of37% in those same movements at the high dose (275 mg/kg).

e) Do the patients respond to the phenylalanine challenge with anincrease in TD symptom severity?

The answer is Yes for three out of four patients.

Three patients had an increase in TD symptom severity (ranging from 69%to 440%) after the Phe challenge. The fourth patient who did not wasagain Patient B with coexisting TD and tardive dystonia.

It is known from the inventor's work in a clinic environment thatpatients with coexisting TD and tardive dystonia have an atypical TDpharmacology in that their TD movements decrease along with theirtardive dystonia symptoms when treated with antiparkinson agents fortheir tardive dystonia. More typically, TD movements increase withincreases in antiparkinson agents. It is consistent thus that the onepatient with coexisting TD and tardive dystonia had a response patternin the multi-challenge protocol opposite to that of the other patients.One patient in Study Five with coexisting TD and tardive dystonia(Example 4, infra) also showed a parallel response between TD andtardive dystonia symptoms, however, that response was to two weeks ofBCAA treatment. Further, a small number of patients enrolled in StudyThree had tardive dystonia. Data on how these patients responded to aPhe challenge (TD-yes and TD-no patients) is presented in Example 4,infra.

The BCAA powder given in orange juice and in the flavored formulation at150 mg/kg and 275 mg/kg consisted of 30 parts--valine, 30parts-isoleucine and 40 parts-leucine.

EXAMPLE 3--Pilot Treatment Trial

A two-week open trial was carried out with administration of a 209 mg/kgdose (three times a day) of the BCAA dietary supplement (amounts ofindividual BCAA as in Example 1) in four male psychotic patients with TD(Study Five) to primarily treat their tardive dyskinesia symptoms, andsecondarily to monitor the effect of the treatment on the otherneuroleptic-induced movement disorders that the patient may have such asparkinsonism, akathisia and tardive dystonia.

Section I. Protocol

                  TABLE 1    ______________________________________    Pilot Treatment Trial Schedule    ______________________________________    A. Baseline phase    Daily: Food diary kept by research nurses and    observation of movement disorder status.    ______________________________________    Day 1 Mon        Baseline Medical exam (inc. CBC; SMAC,                     Urinalysis)    Day 2 Tues            8:30 AM  1st Baseline Videotaped TD Movement Count                     1st Baseline Videotaped Movement Disorder                     Scale Evaluations    Day 3 Wed            7:00 AM  Plasma LNAA, neuroleptic level, glucose level                     Weigh patient, Phe challenge dose            8:30 AM  Videotaped TD Movement Count                     Videotaped Movement Disorder Scale                     Evaluations            9:00 AM  Plasma LNAA, glucose level    Day 4 Thurs      Baseline BPRS, HAM-D, MMSE, SANS    Day 9 Tues            8:30 AM  2nd Baseline Videotaped TD Movement Count                     2nd Baseline Videotaped Movement Disorder                     Scale Evaluations    ______________________________________    B. Treatment Phase    Daily: 209 mg/kg dose t.i.d. administered, Food diary    kept by research nurses, vital signs taken, and health    and psychiatric status monitored.    ______________________________________    Days 10, 17, & 24               7:00 AM  Fasting Plasma LNAA, neuroleptic                        level, glucose level    Wed                 Weigh patient; AM dose of BCAA or                        placebo given               8:30 AM  Treatment Videotaped TD Movement                        Count                        Treatment Videotaped Movement Dis-                        order Scale Evaluations               9:00 AM  Plasma LNAA, glucose level    Day 10-Day 23       BCAA or Placebo t.i.d. given 1 hr.                        before each meal    Day 18 Thurs        Treatment-BPRS, HAM-D, MMSE,                        SANS    Day 25 Thurs        Post-study medical exam (inc. CBC;                        SMAC, Urinalysis)    ______________________________________

Section II. Effect of Treatment on Tardive Dyskinesia

The outcome of this trial, to date, on TD symptoms is set forth in Table2, below. The TD movement counts presented to define response were ratedfrom the videotapes, using carefully constructed evaluation methodology.A 50% or more decrease in this count was classified as a response to thetreatment. A minimum of a 50% decrease in TD count was selected todefine a clinically meaningful measure of efficacy rather than a merelystatistically significant one. The efficacy designation was based on thepercent change between the average of the two fasting TD counts onbaseline DAYS 2 and 9 and the TD count after the last dose of treatment(DAY 31). Frequency counts have long been in use in treatment trials forTD. The present inventor has published the particular frequency countmethodology that was used. (Richardson, M. A., Craig, T. J., Branchey,H. H., "Intra-patient variability in the measurement of tardivedyskinesia," Psychopharmacology, 76:269-272, 1982). In that publication,the issue of how to compensate for intrapatient variability in treatmenttrials was analyzed from several viewpoints. It was demonstrated thatfrequency counts of eight minutes minimize to only 6% the chance of afalse efficacy designation (counts of 30 seconds have a 22% chance).

The TD movement counts were made over a total period of 8 minutes ofobservation for each patient and consist of two four-minute counts oforal/facial movements for each patient. Oral/facial movements,particularly those of the tongue, are considered to be mostpathognomonic of TD and are the least diagnostically contaminated byvoluntary movements, stereotypies, or movements due to another syndrome.Each patient had a countable tongue movement. For three of the patients,the second movement was that of the lips, while for one it was the jaw.Baseline counts were the average of two baseline rating sessions.

Section A of Table 2 shows the actual movement counts at each evaluationpoint, while Section B of Table 2 shows the percent change from baselineat each evaluation point. The first evaluation point was two hours afterthe first treatment; the second after a full week of treatment and thethird after two full weeks of treatment. These evaluation points wereselected to allow examination issues such as the relationship of acutebenefit to chronic benefit, the continuance of acute benefit, theanticipated duration of effect, and the adaptive changes to treatmentover time. While the four patients showed individual patterns ofresponse, there were, nevertheless, some commonalities. Though oursample numbers are too small to establish a rule, on the issue of therelationship of acute benefit to chronic benefit it is interesting tonote that while a strong acute response is a predictor of a two-weektreatment response, a weak or moderate one gives no information aboutthe two-week response. On the issues of continuance of acute benefit andadaptive changes over time, note that while AJ, SB and PG showed sometolerance after one week from their acute response, VS showed furtherimprovement. AJ went on to improve beyond the acute response by the endof the second week. While SB improved further at the end of the secondweek, that second week response was still not as good as his acuteresponse. PG clearly needed the two-week treatment period to demonstrateany treatment response, showing a sharp drop in symptoms after thesecond week. VS showed a consistent decrease in symptoms at eachevaluation point. On the issue of duration of effect (a) AJ and SB had atreatment effect acutely that lasted for two weeks, (b) it took PG twofull weeks of treatment to meet our response criterion of a 50% decreasein symptoms, and (c) VS needed a full week of treatment to achieveresponder status and then improved further after two full weeks oftreatment. The common elements across the patients are (a) that thistreatment reduced TD symptoms and (b) two weeks of treatment is betterthan one.

In summary, the Pilot Treatment Trial data have shown that the BCAA canvery effectively treat TD over a period of two weeks. Moreover, themagnitude and consistency of the symptom reductions seen are new to thefield of TD treatment.

                  TABLE 2    ______________________________________    Pilot Treatment Trial    Oral/Facial TD Movements over a Two-Week Period    Patients    Baseline Two hours                                  One week                                         Two weeks    ______________________________________    A. TD movements count - per 8 minutes    AJ  (Tongue + Jaw)                    82       4      2      1    SB  (Tongue + Lips)                    28       5      11     8    PG  (Tongue + Lips)                    135      114    141    37    VS  (Tongue + Lips)                    58       39     29     18    B. Percent change in movement counts from baseline    AJ  (Tongue + Jaw)       -95.1  -85.4  -98.8    SB  (Tongue + Lips)      -82.1  -60.7  -71.4    PG  (Tongue + Lips)      -15.6  4.4    -72.6    VS  (Tongue + Lips)      -32.8  -50.0  -69.0    ______________________________________

Section II. Effect of the BCAA Treatment on Parkinsonism

Three of the above-listed patients (SB, PG and VS) made criteria for thepresence of Parkinsonism. A fourth patient (DB) who also manifested thedisorder was not shown above because he only completed one week oftreatment. Following are the results of the BCAA treatment on theParkinsonism symptoms of those patients.

                  TABLE 3    ______________________________________    Pilot BCAA Treatment Trial    Total Parkinsonism Score over a Two-Week Period    Patients Baseline Two hours  One week                                        Two weeks    ______________________________________    A. Total Score: Neurological Rating Scale    SB       5        4          0      0    PG       15       11         13     10    VS       4        4          4      5    DB       5.5      1          0    B. Percent change in total Parkinsonism score from baseline    SB                -20.0      -100.0 -100.0    PG                -26.7      -13.3  -33.3    VS                0.0        0.0    +25.0    DB                -81.8      -100.0    ______________________________________

Section III. Effect of the BCAA Treatment on Akathisia

None of the study patients showed symptoms of akathisia on both of theirtwo baseline days. One patient, however, did show the disorder on thebaseline day closest to beginning BCAA treatment (the day beforetreatment started). This patient (JS), who was not a study completer anddid not have Parkinsonism, showed mild akathisia symptoms at baseline(global score of 2), which decreased to very mild (global score of 1)after the first treatment and returned to mild symptoms (global score of2) after one week of treatment.

Section IV. Effect of the BCAA Treatment on Tardive Dystonia

Only one patient (PG) showed dystonia symptoms at baseline and only onthe one baseline day that was closest to beginning BCAA treatment. Thispatient had a moderate level of symptoms at baseline (global score of 3)which disappeared after the first treatment dose (global score of 0),returned at one week to the baseline level and declined after two weeksof treatment to a mild designation (global score of 2, -44.4%).

EXAMPLE 4

Study Three (n=312; 209 men and 103 women) as noted above demonstratedthat the metabolic response to a phenylalanine challenge (100 mg/kg)significantly distinguished males with TD from those without thedisorder, thus establishing phenylalanine metabolism as apathophysiological element in TD. As shown below, the data from thisstudy has also enabled the present inventor to study the effect of thephenylalanine challenge on the symptom levels of Parkinsonism, akathisiaand tardive dystonia. This information is important in justifying theusefulness of large neutral amino acid treatments for these disorders.

Section I. Effect of Phenylalanine Challenge on Symptom Levels ofParkinsonism and Treatment Implications

185 (59.3%) of the study patients made criterion for a case ofParkinsonism; 124 men and 62 women. Two hours subsequent to thephenylalanine challenge, 21 patients (11.3%) showed no change in,symptoms; 79 patients (42.7%) showed an improvement in symptoms, and 85(45.9%) patients showed a worsening in symptoms. The large percentage(88.6%) of patients whose symptoms were impacted by the phenylalaninechallenge supports the value of plasma large neutral amino acidmanipulation in the treatment of this disorder. Further, as is seen inTable 3 below, this pattern of change was quite similar whether or notthe patient had coexisting tardive dyskinesia. Though there is a case bycase aspect to treatment success which makes prediction difficult, onecan set forth some predictive generalizations as below. A further caveatis that because of the possible case of the worsening of a coexistingdisorder the clinician must first treat the disorder that is causing thepatient the most difficulty. Difficulty would be defined by someinteraction between severity of symptom and disorder.

a. Possible treatment modalities for patients whose Parkinsonismsymptoms worsened after a phenylalanine challenge whether or not theyshowed coexisting TD:

It is reasonable to expect (given the a success of the Berry, et al.work noted above in the treatment of PKU with the BCAA, and theinventor's own success in treating TD with the BCAA as shown in Example3 above) that these patients will respond to BCAA treatment with adecrease in symptoms as we saw in 3 out of 4 patients in Example 3above.

b. Possible treatment modalities for patients whose Parkinsonismsymptoms improve after a phenylalanine challenge:

On the other hand, it is also reasonable to expect that this subgroup ofpatients will show improvement with treatments consisting of thearomatic amino acids, phenylalanine and/or tyrosine.

Section II. Effect of Phenylalanine Challenge on Symptom Levels ofAkathisia and Treatment Implications

105 patients (33.7%) showed symptoms of akathisia; 79 men and 26 women.Two hours subsequent to the phenylalanine challenge, 20 patients (19.0%)showed no change in symptoms; 35 (33.4%) showed an improvement insymptoms, and 50 (47.6%) showed a worsening of symptoms. The largepercentage (81.0%) of patients whose symptoms were impacted by thephenylalanine challenge supports the value of plasma large neutral aminoacid manipulation in the treatment of this disorder. As can be seen inTable 3, below, unlike for the Parkinsonism, the presence of coexistingTD did impact on the akathisia symptom response to be phenylalaninechallenge. Patients without coexisting TD were more likely to show ahigher level of symptom worsening than those with coexisting TD. As saidfor Parkinsonism, above, though it is the case that there is a case bycase aspect to treatment success which makes prediction difficult, onecan set forth some predictive generalizations as below:

a. Possible treatment modalities for patients whose akathisia symptomsworsened after a phenylalanine challenge:

It is reasonable to expect that this subgroup of patients, particularlythose without coexisting TD, will respond to treatment with the BCAA.The one patient with akathisia in Example Three, (who had coexisting TD)did show a decrease after the first dose of BCAA but it did not holdafter one week of treatment.

b. Possible treatment modalities for patients whose akathisia symptomsimproved after a phenylalanine challenge:

It is reasonable to expect that this subgroup of patients, especiallythose with coexisting TD, will respond to treatments consisting of thearomatic amino acids, phenylalanine and/or tyrosine.

Section III. Effect of Phenylalanine Challenge on Symptom Levels ofTardive Dystonia and Treatment Implications

Nineteen patients (6.1%) showed symptoms of tardive dystonia; 15 men and4 women. Two hours subsequent to the phenylalanine challenge, 8 patients(42.1%) showed no change in symptom levels while 4 patients (21.0%)improved and 7 patients (36.9%) showed a worsening.. Thus, more than amajority of patients (57.9%) did respond to the phenylalanine challenge.As can be seen in Table 3 below, the presence of coexisting TD markedlychanged the response of tardive dystonia symptoms to a phenylalaninechallenge. Patients without coexisting TD were much more likely toimprove their tardive dystonia symptom status after a phenylalaninechallenge than patients with coexisting TD, while patients withcoexisting TD were much more likely to show a higher level of symptomworsening than those without coexisting TD.

a. Possible treatment modalities for patients whose tardive dystoniasymptoms worsened after a phenylalanine challenge:

In the BCAA treatment trial presented in Example 3 above, the onepatient with tardive dystonia (and coexisting TD) did show a 44.4%decrease in dystonia symptoms after two weeks of BCAA treatment. Giventhese data and those in Table 3 below, it is thus reasonable to expectthat patients whose symptoms worsened after a phenylalanine challenge,especially those with coexisting TD (none of the Study Three patientswith tardive dystonia and without TD showed worsening after aphenylalanine challenge), would so respond to BCAA treatment.

b. Possible treatment modalities for patients whose tardive dystoniasymptoms improved after a phenylalanine challenge:

As we can see in Table 3, below, it is reasonable to expect that thissubgroup of patients, particularly those without coexisting TD, wouldresponse to treatments consisting of the aromatic amino acids,phenylalanine and/or tyrosine.

                  TABLE 3    ______________________________________    The Effect of a Phenylalanine Challenge (100    mg/kg) on the Symptoms of Parkinsonism,    Akathisia, and Tardive Dystonia             ALL      TD-YES     TD-NO             No.  %       No.    %     No.  %    ______________________________________    PK    BETTER     79     42.7    45   44.5  34   40.5    WORSE      85     45.9    46   45.6  39   46.4    NO         21     11.4    10   9.9   11   13.1    CHANGE    TOTAL      185            101        84    AKA    BETTER     35     33.4    25   39.7  10   23.8    WORSE      50     47.6    25   39.7  25   59.5    NO         20     19.0    13   21.6  7    16.7    CHANGE    TOTAL      105            63         42    DYSTONIA    BETTER     4      21.0    1    7.1   3    60.0    WORSE      7      36.9    7    50.0  0    0.0    NO         8      42.1    6    42.9  2    40.0    CHANGE    TOTAL      19             14         5    ______________________________________

Technical aspects of invention

While the invention has been illustrated with administration of amixture of valine, isoleucine and leucine in nearly equal parts, thebenefits of the present invention are realized by administration of atleast one of valine, isoleucine and leucine. Further, when a mixture isemployed, the ratio of a 2 component and 3. component mixture is inparts by weight 1:100 to 100:1 for a 2-component mixture and for a3-component mixture, a ratio of by weight of 1:100 to 100:1 for each ofthe three sub-ratios possible for a 3-component mixture.

The total amount of the branched chain amino acids to be administered,based on molecular weights about those of valine, isoleucine andleucine, is about 50 to 1500 mg/kg of body weight daily, administered inone dose or subdivided into 3 or 4 subdoses spread throughout the day.The branched amino acids can be administered in the form of variouspharmaceutical preparations such as tablets, capsules, flavored bars,suspensions, emulsions, etc. Liquid formulations can be prepared bymixing amino acid powder with various liquids such as water and juicessuch as orange juice, etc. Since the dosage is best optimized for anindividual patient, a suggested starting dosage is about 150 to 275mg/kg per day followed by weekly patient monitoring with increasing ordecreasing the dosages in increments of about 50 mg/kg/day as presenceor absence, increase or decrease, of symptoms is evaluated, therebyreaching the lowest effective dose.

Also, the present invention contemplates the substitution of syntheticamino acids/compounds of chemical structure differing from that of thenaturally occurring amino acids for all or part of the aforementionednaturally occurring amino acids if the synthetic analogs/compounds canbe shown by routine experimentation to function in an equivalent mannerto the naturally occurring amino acids described herein, but withenhanced efficacy, safety or pharmacokinetics. The synthetic analogs maybe characterized by, but are not restricted to, modifications of thestructural nucleus of the branched chain amino acids, which have basicformula NH₂ CH(X)COOH, where X contains a secondary or tertiary carbonatom and contains 3 to 5 carbon atoms, and will be shown to function ina manner analogous (i.e., having similar mechanism of action) of thenaturally occurring amino acids.

Although, at this time it is believed that the branched chain aminoacids will be useful in most cases of neuroleptic-induced TD, thisprediction becomes more complex in the case of coexisting disorders. InStudy Four, Example Two above, one patient with coexisting TD andtardive dystonia showed a TD symptom worsening with the administrationof BCAA, but did not show a symptom increase when challenged withphenylalanine. It may be, thus, that this patient may thus improve iftreated with one of the aromatic amino acids, phenylalanine or tyrosine,as discussed with the TD-yes patients of Table 3 having co-existingdystonia. On the other hand, in Study Five, Example Three, we see thepatient PG who also had coexisting TD and tardive dystonia improve inboth his TD and tardive dystonia symptoms after two weeks of BCAAtreatment, thus, further emphasizing the case by case approach neededfor treatment with these movement disorders.

The complexities of treatment in this field are further demonstrated bythe data presented in this application on neuroleptic-inducedparkinsonism. In Study Three, Example 4, 79 patients with parkinsonismshowed a decrease in Parkinsonism symptoms after a Phe challenge, whichwould support the use of aromatic acids to treat parkinsonism. Thisfinding is consistent with results in some other limited work done priorto Study Three in which the present inventor found that in one patientthe administration of a high caloric dietary food product rich in BCAA,while it markedly improved TD symptoms, had increased the symptoms ofparkinsonism; thus, further supporting the use of aromatic amino acidsto treat Parkinsonism. However, we have also unexpectedly seen that inStudy Five, Example 3, three out of four patients with coexisting TD andParkinsonism had parallel decreases in TD and Parkinsonism with twoweeks of BCAA treatment. Further, we have seen in Study Three, Example4, that 85 patients with Parkinsonism (46% of those showing thedisorder) responded to a Phe challenge with a worsening in symptoms,thus, supporting in some patients the use of the BCAA to treat symptomsof the disorder. This is consistent with the findings of Lakke andTeelken, 1976, that Phe is elevated in idiopathic Parkinson's disease.

The present inventor had also found in the limited work done with theadministration of a high caloric dietary food product rich in BCAA thatin one patient the symptoms of akathisia had markedly increased as TDimproved. This, plus the akathisia data presented in Example 4 in Table3, along with what is known about the competition between the BCAA andthe aromatic amino acids for brain entrance, suggests that akathisia, adisorder which is most always very troublesome for patients and hasproven difficult to treat, might respond in some patients to treatmentwith the aromatic LNAA and in other to the BCAA.

This illustrates the broad applicability of the present invention intreating various abnormal movement disorders by manipulating the aminoacids in the blood plasma pool in various ways, for example, at timesthrough the administration of branched chain amino acids and at othertimes through the administration of aromatic amino acids. The aromaticamino acids will be administered in an amount of about 50 to 1,500 mg/kgof body weight daily, administered in one dose or subdivided into threeor four subdoses spread throughout the day.

While the studies and examples presented have been concerned withabnormal movement disorders which arise secondary to drugadministration, especially secondary to treatment with neuroleptics, itis apparent to those of ordinary knowledge in this field that thetreatments proposed are also applicable to abnormal movement syndromeswith similar phenomenology when they arise either from (1) treatmentwith drugs other than neuroleptics, and (b) neurological disorders,primarily those of basal ganglia origin.

a. Abnormal movement syndromes that arise from treatment with drugsother than neuroleptics that our proposed branched chain or aromaticamino acids treatments are appropriate for are:

1. Dyskinesias that have been seen to arise from treatment with drugssuch as anticholinergics, antihistaminics and phenytoin.

2. Parkinsonism that has been seen to arise from treatment with drugssuch as captopril, lithium, and phenytoin.

3. Akathisia that has been seen to arise from treatment with drugs suchas methysergide and levodopa.

4. Dystonia that has been seen to arise from treatment with drugs suchas levodopa, phenytoin, and carbamzepine.

b. Our proposed branched chain or aromatic amino acids treatments areappropriate for the following abnormal movement syndromes that arisefrom neurological disorders or other disease and age related processes:

1. The symptomatology of dyskinesias such as the spontaneouslingual/facial/buccal dyskinesias seen in the elderly, and theoral/facial dyskinesias seen in patients with Alzheimer's disease areindistinguishable from tardive dyskinesia. This commonality in clinicalfeatures and some hypothesized commonality in pathophysiology will leadto the use of the BCAA in these other non-neuroleptic-induced disordersparticularly in the face of a lack of existing successful and safetreatment modalities.

2. Dystonias other than tardive dystonia such as idiopathic torsiondystonia are, in fact, being treated with drugs such as trihexyphenidylbecause of its original use in treating neuroleptic-induced tardivedystonia (Fahn, S., "High dosage anticholinergic therapy in dystonia,"Neurology, 1983, 33: 1255-1261). Thus, success with our large neutralamino acid treatments in tardive dystonia leads to use of thesetreatments by neurologists for primary neurological disorders such astorsion dystonia.

3. Idiopathic akathisia (restless legs syndrome): A drug that is used totreat this disorder, propranolol, has been used to treatneuroleptic-induced akathisia and has been successful in some patients.(Weiner, W. J. and Lang, A. E., Movement Disorders, A comprehensivesurvey, Mt. Kisco, N.Y., 1989, pp. 569-685). Thus, success with ourlarge neutral amino acid treatments in neuroleptic-induced akathisialeads to the use of these treatments by neurologists to treat idiopathicakathisia.

4. Parkinsonism: The clinical features of neuroleptic-inducedParkinsonism are virtually indistinguishable from idiopathic Parkinson'sdisease. It was in fact the knowledge of this neuroleptic-inducedParkinsonism that eventually led to the discovery of the importance ofdopamine deficiency in the manifestations of idiopathic Parkinson'sdisease (Weiner & Lang, 1989). Neuroleptic-induced Parkinsonism as wellas idiopathic Parkinson's disease are both presently treated withanti-parkinson drugs such as benztropine and trihexyphenidyl. Thus,success with our large neutral amino acid treatments forneuroleptic-induced Parkinsonism leads to use of those treatments byneurologists for idiopathic Parkinson's disease.

While the invention has been described in detail, and with reference tospecific embodiments thereof, it will be apparent to one of ordinaryskill in the art that various changes and modifications can be madetherein without departing from the spirit and scope thereof.

What is claimed is:
 1. A method of treating an abnormal movementdisorder which arises as a symptom of a primary neurological disorder,which method comprises administering to a patient having such movementdisorder an amino acid selected from the group consisting ofphenylalanine and tyrosine in an amount sufficient for treating saidabnormal movement disorder.
 2. The method of claim 1, wherein the aminoacid is administered in the form of an amino acid enriched meal.
 3. Themethod of claim 1, wherein the amino acid is administered in the form ofa dietary supplement.
 4. The method of claim 1, wherein the primaryneurological disorder is selected from the group consisting of aParkinson's Disease tic disorder, Huntington's Disorder, MyoclonicSyndrome, a dystonia, Wilson's Disease, a chorea, Alzheimer's Disease,Creutzfeldt-Jakob Disease, Pick's Disease, Tourette's Syndrome andHallervorden Spatz Disease.
 5. The method of claim 1, wherein themovement disorder is caused by basal ganglia disease.
 6. The method ofclaim 1, wherein the amino acid is phenylalanine.
 7. A method oftreating an abnormal movement disorder which arises as a symptom of aprimary neurological disorder selected from group consisting ofParkinson's Disease, a tic disorder, Myoclonic Syndrome, a dystonia,Wilson's Disease, a chorea other than Huntington's Disorder,Creutzfeldt-Jakob Disease, Pick's Disease, Tourette's Syndrome andHallervorden Spatz Disease, which method comprises administering to apatient having such movement disorder at least one branched chain aminoacid, phenylalanine or tyrosine.
 8. The method of claim 7, wherein thebranched chain amino acid is selected from the group consisting ofisoleucine, leucine and valine.
 9. The method of claim 7, wherein amixture of isoleucine, leucine and valine is administered.
 10. Themethod of claim 7, wherein the branched chain amino acid is administeredin an amount of about 50 mg/kg/day to 1500 mg/kg/day.
 11. The method ofclaim 7 wherein the branched chain amino acid is administered in theform of an amino acid enriched meal.
 12. The method of claim 7 whereinthe branched chain amino acid is administered in the form of a dietarysupplement.
 13. The method of claim 7 wherein the movement disorder iscaused by Basal Ganglia Disease.
 14. The method of claim 7 wherein atleast one branched chain amino acid is administered.
 15. The method ofclaim 7 wherein phenylalanine is administered.
 16. The method of claim 7wherein tyrosine is administered.
 17. A method of treating an abnormalmovement disorder which arises as a symptom of a primary neurologicaldisorder selected from the group consisting of Parkinson's Disease, atic disorder, Myoclonic Syndrome, a dystonia Wilson's Disease, a choreaother than Huntington's Disorder, Alzheimer's Disease. Creutzfeldt-JakobDisease, Pick's Disease, Tourette's Syndrome and Hallervorden SpatzDisease, which method comprises altering plasma levels of the aromaticamino acid phenylalanine, tyrosine and/or tryptophan of a patient havingsuch movement disorder by administering at least one branched chainamino acid, phenylalanine or tyrosine to the patient in an amountsufficient for altering said plasma levels sufficiently for treatingsaid movement disorder.
 18. The method of claim 17 wherein the aminoacid is administered in the form of an amino acid enriched meal.
 19. Themethod of claim 17 wherein the amino acid is administered in the form ofa dietary supplement.
 20. The method of claim 17 wherein the branchedchain amino acid is selected from the group consisting of isoleucine,leucine and valine.
 21. The method of claim 17 wherein the movementdisorder is caused by Basal Ganglia Disease.
 22. The method of claim 17wherein at least one branched chain amino acid is administered.
 23. Themethod of claim 17 wherein phenylalanine is administered.
 24. The methodof claim 17 wherein tyrosine is administered.
 25. A method of treatingan abnormal movement disorder which arises as a symptom of a primaryneurological disorder, selected from the group consisting of Parkinson'sDisease, a tic disorder, Myoclonic Syndrome, a dystonia, Wilson'sDisease, a chorea other than Huntington's Disorder, Alzheimer's Disease,Creutzfeldt-Jakob Disease, Pick's Disease, Tourette's Syndrome andHallervorden Spatz Disease, which comprises decreasing uptake of thearomatic amino acid phenylalanine, tyrosine and/or tryptophan at theblood brain barrier by administering at least one branched chain aminoacid to a patient having such movement disorder in an amount sufficientfor decreasing said uptake sufficiently for treating said abnormalmovement disorder.
 26. The method of claim 25 wherein the branched chainamino acid is administered in the form of an amino acid enriched meal.27. The method of claim 25 wherein the branched chain amino acid isadministered in the form of a dietary supplement.
 28. The method ofclaim 25 wherein the branched chain amino acid is selected from thegroup consisting of isoleucine, leucine or valine.
 29. The method ofclaim 25 wherein the movement disorder is caused by Basal GangliaDisease.
 30. A method of treating an abnormal movement disorder whicharises as a symptom of a primary neurological disorder selected from thegroup consisting of Huntington's Disorder, childhood and adult onsetdystonias, Wilson's Disease, a chorea, Alzheimer's Disease,Creutzfeldt-Jakob Disease and Hallervorden Spatz Disease which comprisesadministering to a patient having said movement disorder tryptophan inan amount sufficient for treating said movement disorder.